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Dissertation
The effect of thrombospondin-1 on tumor cell metastasis: downstream mediators of TSP-1
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Apr 1999
DOI:
https://doi.org/10.17918/00008457
Abstract
Thrombospondin-1 (TSP-1) is a 450 kDa glycoprotein involved in a variety of processes, including cell adhesion, tumor progression, and angiogenesis. Many laboratories cite evidence that TSP-1 serves as an inhibitor of angiogenesis and tumor metastasis; however, evidence from our laboratory and from that of others show that TSP-1 is actually a potent stimulator of tumor progression and has a biphasic role with regards to angiogenesis. Evidence from our laboratory include: (1) TSP-1 promotes lung metastasis in a murine model; (2) TSP-1 modulates tumor cell adhesion; and (3) TSP-1 modulates proteolytic enzyme levels in human tumor cells and these enzymes influence tumor cell invasion. Some of the enzymes modulated by TSP-1 include components of the plasmin/plasminogen system and also matrix metalloproteinase 9 (MMP-9). The work presented here examined two aspects of TSP-1 mediated tumor progression including the capacity of TSP-1 to maintain a controlled proteolytic environment necessary for tumor cell in invasion and the capacity of TSP-1 to modulate tumor cell adhesion to the extracellular matrix. Chapter 2 describes a series of experiments designed to show that TSP-1 upregulates tissue inhibitor of metalloproteinase 1 (TIMP-1), the physiological inhibitor of MMP-9. We show through western and ELISA analysis that TSP-1 modulates TIMP-1 production in a dose dependent manner. In addition, TSP-1 is able to up-regulate TIMP-1 message as well. This property of TSP-1 through a series of antibody and peptide inhibition studies was found to be associated with the CSVTCG domain of type I repeats of TSP-1. Chapter 3 of this thesis describes the novel discovery that TSP-1 is able to regulate breast cancer cell adhesion to components of the ECK specifically laminin. TSP-1 is able to up-regulate expression of the integrin [special characters omitted] subunit which is the [special characters omitted] subunit of a group of laminin receptors, [special characters omitted] and [special characters omitted] integrins. This property of TSP-1 was observed at both the message and protein levels of a series of stably transfected MDA-MB-435 breast carcinoma cells. These cells are able to produce varying levels of TSP-1 and this expression pattern correlated with [special characters omitted] expression in these cells. Functionally, cells with higher TSP-1 production showed increased adhesion to laminin and also increased invasion through a laminin matrix. TSP-1 is a complex molecule with many different functions. Despite the controversy surrounding this molecule in the fields of tumor progression and aniogenesis, we maintain the role of TSP-1 as a potentiator of tumor cell metastasis. The hypothesis presented here is that TSP-1 modulates tumor cell progression through: (1) creating a controlled proteolytic environment necessary for tumor invasion through the up-regulation of (TIMP-1) and (2) modulating tumor cell adhesion to laminin through the up-regulation of [special characters omitted] integrin. (Abstract shortened by UMI.).
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Details
- Title
- The effect of thrombospondin-1 on tumor cell metastasis
- Creators
- Anitha Sara John
- Contributors
- George P. Tuszynski (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xv, 123 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888716804721